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Research Papers:

Management of hepatocellular carcinoma: an overview of major findings from meta-analyses

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Oncotarget. 2016; 7:34703-34751. https://doi.org/10.18632/oncotarget.9157

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Xingshun Qi _, Yan Zhao, Hongyu Li, Xiaozhong Guo and Guohong Han

Abstract

Xingshun Qi1,2,*, Yan Zhao2,3,*, Hongyu Li1,*, Xiaozhong Guo1, Guohong Han2

1Department of Gastroenterology and Meta-analysis Study Interest Group, General Hospital of Shenyang Military Area, Shenyang, 110840 China

2Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, 710032 China

3Department of Gastroenterology, First Affiliated Hospital of the Medical College, Xi’an Jiaotong University, Xi’an, 710000 China

*Co-first authors, these authors contributed equally to this work

Correspondence to:

Xingshun Qi, email: xingshunqi@126.com

Xiaozhong Guo, email: guo_xiao_zhong@126.com

Guohong Han, email: guohhan@126.com

Keywords: hepatocellular carcinoma, treatment, management, meta-analysis, systematic review

Received: February 19, 2016     Accepted: April 11, 2016     Published: May 04, 2016

ABSTRACT

This paper aims to systematically review the major findings from meta-analyses comparing different treatment options for hepatocellular carcinoma (HCC). A total of 153 relevant papers were searched via the PubMed, EMBASE, and Cochrane library databases. They were classified according to the mainstay treatment modalities (i.e., liver transplantation, surgical resection, radiofrequency ablation, transarterial embolization or chemoembolization, sorafenib, and others). The primary outcome data, such as overall survival, diseases-free survival or recurrence-free survival, progression-free survival, and safety, were summarized. The recommendations and uncertainties regarding the treatment of HCC were also proposed.


Management of hepatocellular carcinoma: an overview of major findings from meta-analyses | Qi | Oncotarget

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death [13]. Currently, the most widely accepted therapeutic algorithm is derived from BCLC staging system [45], in which the mainstay treatment options for HCC include liver transplantation (LT), surgical resection, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), transarterial embolization (TAE) or chemoembolization (TACE), and sorafenib. Several novel therapeutic modalities have been also explored, such as percutaneous acetic acid injection (PAI), three-dimensional conformal radiation therapy (3D-CRT), argon-helium cryotherapy system (AHCS), traditional Chinese medicine (TCMs), cytokine-induced killer (CIK) cell therapy, and portal vein embolization (PVE), etc. It remains unclear about whether or such novel therapeutic modalities could be applied to the clinical practice. Meta-analysis can provide the highest level of evidence for our clinical decisions by combining all scattered data [67]. Herein, we systematically reviewed the major findings from all meta-analyses regarding the treatment of HCC and attempted to propose the evidence-based recommendations and uncertainties.

RESULTS

Overall, 2039 papers were identified. Among them, 153 meta-analysis papers were finally included [8160] (Figure 1). The number of relevant papers was gradually increased over years (Supplementary Figure S1). The characteristics of these included papers were shown in Table 1. Their major findings were summarized according to the treatment modalities (Tables 25 and Supplementary Tables S1–S8).

Flowchart of study inclusion.

Figure 1: Flowchart of study inclusion.

Table 1: Study characteristics: An overview of included studies

First author

Journal (Year)

Country

Type of participants

No. included studies/pts.

Comparisons

Type of studies

RCT

Non-RCT

Al Hasan

Liver Transpl (2014)

Saudi Arabia

Unselected HCC

7/1388

Living donor LT vs deceased donor LT

0

7

Bouza

BMC Gastroenterol (2009)

Spain

Early, small HCC

6/787

RFA vs PEI

6

0

Breitenstein

Br J Surg (2009)

Switzerland

Unselected HCC

7/620

Interferon after resection or ablation

7

0

Cai

HPB (2013)

China

HCC ≤ 5 cm

5/NA

RFA vs surgical resection

NA

NA

Camma

Radiology (2002)

Italy

Unresectable HCC

18/2466

TACE vs non-active treatment; different transarterial modalities of therapy (TACE, TCE, TAE)

5; 13

0

Cao

Ultrasound Med Biol (2011)

China

Unselected HCC

9/736

TACE plus HIFU vs TACE alone

0

9

Chen

Dig Dis Sci (2011)

China

Unselected HCC

9/1503

Anatomic vs nonanatomic resection

0

9

Chen

Zhonghua Wai Ke Za Zhi (2008)

China

HCC ≤ 5 cm, number of lesions ≤ 3

6/697

RFA vs surgical resection

1

5

Chen

Chinese-German Journal of Clinical Oncology (2013)

China

Unresectable HCC

9/870

CIK cell + TACE

9

0

Cheng

J Cancer Res Clin Oncol (2014)

China

Resectable HCC

10/909

Preoperative TACE vs control; postoperative TACE vs control

4; 6

0; 0

Cheung

Evid Based Complement Alternat Med (2013)

China

Unresectable HCC

67/5211

TACE + Chinese medicines vs TACE alone

67

0

Cho

Hepatology (2009)

Korea

Unselected HCC

4/652

RFA vs PEI

4

0

Cho

Expert Opin Investig Drugs (2009)

China

HCC patients receiving TACE

30/2428

TACE + Chinese herbal therapy vs TACE alone

30

0

Chu

Asian J Surg (2010)

China

Post-operative HCC

5/206

Vitamin analogues (vitamin A and K2) after hepatic resection or local ablative therapy

5

0

Cinco

Hepatology International (2011)

Philippines

Advanced HCC

2/828

Sorafenib vs placebo

9

0

Cucchetti

Ann Surg Oncol (2012)

Italy

Unselected HCC

18/9036

Anatomic vs nonanatomic resection

0

18

Cucchetti

J Hepatol (2013)

Italy

Early HCC ≤ 5 cm

17/8420

RFA vs surgical resection

NA

NA

Dhir

HPB (2012)

USA

Early HCC within Milan Criteria

10/1763

LT vs resection

0

10

Dong

World J Gastroenterol (2014)

China

Unselected HCC

22/NA

Surgical resection vs nonsurgical-resection ablation therapies; RFA vs PEI; RFA vs RFA+TACE

2; 5; 0

10; 0; 5

Duan

World J Surg Oncol (2013)

China

Unselected HCC

12/8612

RFA vs surgical resection

2

12

Duffy

Hepatology (2013)

USA

Unselected HCC

6/2464

Antiangiogenic agents vs placebo

6

21

Estanislao

J Gastroenterol Hepatol (2009)

Philippine

Advanced HCC

NA/NA

Octreotide vs no octreotide

NA

NA

Fancellu

J Surg Res (2011)

Italy

Resectable HCC

9/590

Minimally-invasive vs open hepatectomy

0

9

Feng

J Cancer Res Clin Oncol (2014)

China

Small HCC (1 lesion < 6.5 cm; no more than 3 lesions < 4.5 cm)

23/15482

RFA vs surgical resection

3

20

Flores

J Gastroenterol Hepatol (2009)

Philippines

Post-operative HCC

2/236

Adjuvant immunotherapy in combination with surgical resection

2

0

Fu

Hepato-gastroenterology (2014)

China

Small HCC (single < 6.5 cm, or ≤ 3 lesions, ≤ 4.5 cm)

5/776

RFA vs surgical resection

5

0

Fu

J Cancer Res Clin Oncol (2014)

China

Unselected HCC

9/900

TACE + sorafenib vs TACE alone

5

4

Fu

J Cancer Res Ther (2014)

China

Unresectable HCC

9/608

Kanglaite injection plus hepatic arterial intervention vs hepatic arterial intervention alone

0

9

Furtado

Ann Surg Oncol (2014)

Australia

Unselected HCC

5/334

Surgery + Adjuvant I(131) lipiodol vs surgery alone

2

3

Gao

Hepato-gastroenterology (2013)

China

Unresectable HCC

7/693

DEB-TACE vs conventional TACE

0

7

Germani

J Hepatol (2010)

UK

Unselected HCC

8/1035

RFA vs PEI; Percutaneous acetic acid injection vs PEI

5; 2

0; 0

Geschwind

Am J Clin Oncol (2003)

USA

Unselected HCC

4/268

Therapeutic embolization vs supportive care alone

4

0

Gong

Nucl Med Commun (2014)

China

Unselected HCC

6/466

Adjuvant therapy with intra-arterial iodine-131-labeled lipiodol ((131)I-lipiodol) to hepatic resection

2

8

Grant

Clin Transplant (2013)

Canada

Unselected HCC

16/2202

Living donor LT vs deceased donor LT

0

16

Gu

J Cancer Res Clin Oncol (2014)

China

Unselected HCC

18/2120

TACE + local ablative therapy vs monotherapy

7

11

Guo

J Cancer Res Clin Oncol (2009)

China

Advanced HCC

6/352

Octreotide vs placebo or best supportive care

6

0

Han

Journal of Interventional Radiology (China) (2013)

China

Unselected HCC

8/698

RFA + TACE vs TACE

0

8

Han

PLoS One (2014)

China

Unresectable HCC

5/454

DEB-TACE vs conventional TACE

3

2

Hoshida

Hepatology (2000)

Japan

Non-advanced HCC

17/NA

Surgical resection vs PEI; Surgical resection vs LT

0; 0

5; 12

Hu

HPB (2013)

China

Unselected HCC

18/NA

RFA vs surgical resection

4

14

Huang

Hepato-gastroenterology (2013)

China

Unselected HCC

4/433

RFA vs cryosurgery ablation

0

4

Huang

J Gastroenterol Hepatol (2014)

China

Unresectable HCC

7/700

DEB-TACE vs conventional TACE

2

5

Huang

J Viral Hepat (2013)

China Taiwan

Unselected HCC

22/3156

Adjuvant interferon therapy after curative treatment

10

13

Huang

Zhonghua Nei Ke Za Zhi (2008)

China

Early HCC within Milan Criteria

6/862

RFA vs other therapeutic methods

6

0

Ji

Med Sci Monit (2011)

China

Advanced HCC

9/759

Octreotide vs placebo or no treatment

9

0

Jiang

Tumour Biol (2014)

China

Unselected HCC

19/1728

RFA + TACE vs RFA alone

8

11

Jiang

World J Surg Oncol (2013)

China

Unselected HCC

10/1029

Adjuvant interferon therapy after treatment with surgical resection or TACE

8

2

Kong

Tumour Biol (2014)

China

Unselected HCC

19/1728

RFA + TACE vs RFA alone

8

11

Lan

Journal of Gastroenterology and Hepatology Research (Hong Kong) (2013)

China

Unselected HCC

10/701

Lamivudine treatment vs no antiviral therapy after liver resection or RFA

0

10

Leng

ANZ J Surg (2014)

China

HCC patients with PVTT

5/600

TACE vs control treatment

2

3

Li

World J Gastroenterol (2012)

China

Unselected HCC

11/1013

Primary LT vs salvage LT

0

11

Li

Hepatol Res (2012)

China

Unselected HCC

10/627

Laparoscopic vs open liver resection

0

10

Li

Hepato-gastroenterology (2011)

China

Unselected HCC

4/776

Anatomic vs nonanatomic resection

0

4

Li

J Gastroenterol Hepatol (2012)

China

Unselected HCC

6/877

RFA vs surgical resection

2

4

Li

Chinese Journal of Evidence-Based Medicine (2012)

China

Intermediate-advanced stage

17/907

TACE + thermotherapy vs TACE alone

17

0

Li

Chinese Journal of Evidence-Based Medicine (2013)

China

Intermediate-advanced stage

16/1467

TACE + argon-helium cryotherapy system (AHCS) vs TACE alone; TACE + argon-helium cryotherapy system vs AHCS

15; 7

0

Li

Chinese Journal of Cancer Prevention and Treatment (2013)

China

Unselected HCC

8/818

Adjuvant IFN vs without IFN after curative treatment

8

0

Li

Clin Res Hepatol Gastroenterol (2014)

China

Unresectable HCC

11/936

CIK+TACE+RFA vs TACE+RFA; CIK+TACE vs TACE

6

5

Liang

Liver Transpl (2012)

China

Unselected HCC

7/1310

Living donor LT vs deceased donor LT

0

7

Liang

Liver Transpl (2012)

China

Unselected HCC

5/2950

Sirolimus-based immunosuppression (SRL) after LT vs SRL-free

0

5

Liao

PLoS One (2013)

China

Unselected HCC

28/2497

TACE+PEI vs TACE; TACE+RT vs TACE; TACE+ three-dimensional conformal radiation therapy (3D-CRT) vs TACE; TACE+RFA vs TACE; TACE+HIFU vs TACE

4; 3; 1; 1; 1

5; 4; 5; 0; 4

Liu

World J Gastroenterol (2010)

China

Unselected HCC

10/1522

RFA vs surgical resection

0

10

Liu

Surg Laparosc Endosc Percutan Tech (2010)

China

Unselected HCC

8/1188

RFA vs surgical resection

8

0

Liu

Tumour Biol (2014)

China

Unselected HCC

7/571

RFA + TACE vs RFA alone

7

0

Liu

PLoS One (2014)

China

Unresectable HCC

17/676

TACE + sorafenib vs monotherapy

3

14

Llovet

Hepatology (2003)

Spain

Unresectable HCC

14/1443

TACE vs control treatment; Tamoxifen vs control treatment

7; 7

0; 0

Lu

Eur J Gastroenterol Hepatol (2013)

China

Unselected HCC

7/574

RFA + TACE vs RFA alone

7

0

Ma

Experimental Hematology and Oncology (2012)

China

Unresectable HCC

13/1212

CIK cell therapy vs non-CIK therapy

13

0

Ma

Chinese Journal of Cancer Prevention and Treatment (2011)

China

Post-operative HCC

4/423

Hepatic resection or RFA alone vs surgery + adoptive immunotherapy

4

0

Marelli

Cardiovasc Intervent Radiol (2007)

UK

Unselected HCC

12/NA

TACE vs control treatment; TACE vs TAE alone

9; 3

0

Mathurin

Aliment Pharmacol Ther (2003)

France

Post-operative HCC

21/NA

Adjuvant therapy after curative liver resection

10

11

Meng

Radiother Oncol (2009)

China

Unselected HCC

17/1476

TACE + radiotherapy vs TACE alone

5

12

Meng

Hepatology International (2011)

China

Post-operative HCC

4/209

Vitamin K2 vs placebo after curative treatment

4

0

Meng

J Altern Complement Med (2008)

China

Unresectable HCC

37/2653

TACE + Traditional Chinese Medicine vs TACE alone

NA

NA

Meng

Explore (NY) (2011)

China

Unresectable HCC

12/1008

TACE + Traditional Chinese Medicine vs TACE alone

11

0

Menon

Aliment Pharmacol Ther (2013)

UK

Unselected HCC

5/474

Sirolimus-based immunosuppression (SRL) after LT vs SRL-free

0

5

Miao

World J Gastroenterol (2010)

China

Unselected HCC

16/1224

Adjuvant antiviral therapy after curative therapy

5

8

Miyake

J Viral Hepat (2010)

Japan

Unselected HCC

5/355

Interferon-alpha after curative therapy

3

2

Moriguchi

Hepatology (2006)

Japan

Unselected HCC

4/604

Tumor ablation plus interferon therapy

4

0

Ni

J Cancer Res Clin Oncol (2013)

China

Unselected HCC

10/21494

RFA/PEI (PAT) vs surgical resection

6

4

Ni

World J Gastroenterol (2013)

China

Unselected HCC

8/598

RFA + TACE vs RFA alone

8

0

Ni

J Cancer Res Clin Oncol (2013)

China

Unselected HCC

6/376

RFA + TACE vs RFA or TACE alone

6

0

Nowak

Cochrane Database Syst Rev (2004); Cancer (2005)

Australia

Unresectable HCC

10/1709

Tamoxifen vs placebo/no intervention

10

0

Oliveri

Cochrane Database Syst Rev (2011)

Denmark

Unresectable HCC

9/645

TACE or TAE vs placebo, sham, or no intervention

9

0

Ono

Cancer (2001)

Japan

Post-operative HCC

3/108

Adjuvant chemotherapy after resection

3

0

Orlando

Am J Gastroenterol (2009)

Italy

Small HCC

5/701

RFA vs PEI

5

0

Pang

Chinese Journal of Evidence-Based Medicine (2010)

China

Unselected HCC

7/309

Laparoscopic vs conventional open hepatectomy

0

7

Parks

HPB (Oxford) (2014)

USA

Unselected HCC

15/1002

Laparoscopic vs open liver resection

0

15

Proneth

Ann Surg Oncol (2014)

Germany

Unselected HCC

9/1572

LT vs resection

0

7

Qi

J Clin Gastroenterol (2014)

China

Early-stage HCC

3/559

RFA vs surgical resection

3

0

Rahman

J Gastrointest Surg (2012)

USA

Unselected HCC

9/2279

LT vs resection

0

9

Riaz

BMC Gastroenterol (2012)

Pakistan

Post-operative HCC

5/754

Vitamin K2 or its analogues vs placebo or No vitamin K

5

0

Schoppmeyer

Cochrane Database Syst Rev (2009)

Germany

Early HCC

3/261

PEI vs percutaneous acetic acid injection; PEI vs surgery

2; 1

0; 0

Shen

J Gastroenterol Hepatol (2013)

China

Small HCC < 3 cm

4/766

RFA vs PEI

4

0

Shen

J Clin Gastroenterol (2013)

China

Unresectable HCC

5/1462

Sorafenib vs placebo

5

0

Shen

J Hepatol (2010)

China Taiwan

Unselected HCC

13/1180

Adjuvant interferon therapy after curative therapy

9

4

Shu

Integr Cancer Ther (2005)

USA

Unresectable HCC

26/2079

Chinese herbal medicine + chemotherapy vs chemotherapy alone

24

2

Singal

Aliment Pharmacol Ther (2010)

USA

Unselected HCC

10/645

Interferon after resection or ablation

5

5

Sun

World Chinese Journal of Digestology (2011)

China

Small HCC

11/2965

RFA vs surgical resection

2

9

Sun

PLoS One (2014)

China

Unselected HCC

13/6350

Nucleot(s)ide analogues vs placebo or no treatment after curative treatment

1

12

Sun

Afr J Tradit Complement Altern Med (2012)

China

Unresectable HCC

10/726

TACE + Compound Kushen Injection vs TACE alone

0

10

Tang

Hepato-gastroenterology (2012)

China

Unselected HCC

5/799

Hepatectomy with a margin aiming at 2 cm vs a margin aiming at 1 cm

1

4

Tang

Hepato-gastroenterology (2013)

China

Resectable HCC

12/1829

Anatomic vs nonanatomic resection

0

12

Twaij

World J Gastroenterol (2014)

United Kingdom

Unselected HCC

4/420

Laparoscopic vs open liver resection

0

4

Wang

Hepato-gastroenterology (2011)

China

Unselected HCC

3/257

Preoperative TACE vs control

3

0

Wang

PLoS One (2014)

China

Early HCC

28/11873

RFA vs surgical resection

3

25

Wang N

Med Oncol (2011)

China

Unselected HCC

7/623

TACE + PEI vs TACE alone

7

0

Wang W

Liver Int (2010)

China

Unselected HCC

10/595

TACE + percutaneous ablation therapy (RFA or PEI) vs TACE or percutaneous ablation therapy alone

10

0

Wang

Asian Pac J Cancer Prev (2013)

China

Unselected HCC

4/1382

Sorafenib with or without chemotherapy vs placebo with or without chemotherapy

4

0

Wang

Can J Gastroenterol (2012)

China

Unresectable HCC

4/210

Prophylactic antibiotic treatment vs no prophylactic antibiotic treatment after transarterial therapy

3

1

Wang

Can J Gastroenterol (2013)

China

Post-operative HCC

27/2614

Different adjuvant therapy after potentially curative treatment

27

0

Weis

Cochrane Database Syst Rev (2013)

Germany

Unselected HCC

11/NA

RFA vs surgical resection; RFA vs PEI or RFA vs acetic acid injection; RFA vs microwave ablation; RFA vs laser ablation

3; 6; 1; 1

0; 0; 0; 0

Wong

Aliment Pharmacol Ther (2011)

China

Unselected HCC

9/551

Antiviral treatment vs no anti-viral treatment

0

9

Wu

J Exp Clin Cancer Res (2009)

China

Unresectable HCC

45/3236

Traditional Chinese Medicines vs other treatment

45

0

Wu

J Cancer Res Ther (2014)

China

Unresectable HCC

9/659

TACE + Cinobufacini vs TACE only

0

9

Xie

Tumour Biol (2014)

China

Advanced HCC

5/582

TACE vs TAE

5

0

Xie

J Cancer Res Clin Oncol (2012)

China

Unresectable HCC

13/1840

TACE vs microsphere embolization

7

6

Xie

PLoS One (2012)

China

Post-operative HCC

6/494

Adoptive immunotherapy vs non-immunotherapy after surgery

6

0

Xiong

World J Gastroenterol (2012)

China

Unselected HCC

9/550

Laparoscopic vs open liver resection

0

15

Xu

Journal of Xi’an Jiaotong University (Medical Sciences) (2012)

China

Unselected HCC

9/2145

LT vs resection

0

9

Xu

Hepatobiliary Pancreat Dis Int (2014)

China

Unselected HCC

17/4238

LT vs resection

0

17

Xu

World J Surg Oncol (2012)

China

Early HCC

13/2535

RFA vs surgical resection

2

11

Xu

Eur J Med Res (2014)

China

Small HCC < 5 cm

6/983

RFA vs PEI

6

0

Xu

Hepatol Res (2014)

China

Unselected HCC

9/1565

Adjuvant interferon therapy after surgical treatment

5

4

Xue

BMC Gastroenterol (2013)

China

Advanced HCC with PVTT

8/1601

TACE vs conservative treatment

0

8

Yan

Dig Dis Sci (2012); Dig Dis Sci (2013)

China

Unselected HCC

19/1728

RFA + TACE vs RFA alone

8

11

Yang

Mol Biol Rep (2014)

China

Unresectable HCC

6/1181

TACE + sorafenib vs TACE alone

3

3

Yao

Chinese Journal of Evidence-Based Medicine (2013)

China

Unselected HCC

13/701

Laparoscopic vs open hepatectomy

0

13

Ye

Asian Pac J Cancer Prev (2012)

China

Unselected HCC

11/1576

Anatomic vs nonanatomic resection

0

11

Yin

Ann Surg Oncol (2013)

China

Unselected HCC

15/1238

Laparoscopic vs open hepatectomy

0

15

Yu

Chinese-German Journal of Clinical Oncology (2013)

China

Unselected HCC

7/1347

Preoperative TACE vs control

0

7

Zhang

PLoS One (2014)

China

Unresectable/advanced HCC

6/1254

TACE + sorafenib vs TACE alone

2

4

Zhang

Anticancer Drugs (2010)

China

Advanced HCC

3/924

Sorafenib-based therapy with other agent-based therapy

3

0

Zhang

Hepatobiliary Pancreat Dis Int (2012)

China

Advanced HCC

6/1164

Sorafenib vs placebo

3

3

Zhang

Molecular and Clinical Oncology (2014)

China

Unselected HCC

14/1385

Adjuvant interferon after curative surgery or ablation therapy

9

5

Zhang

Int J Cancer (2009)

China

Post-surgical or ablative HCC

6/600

IFN-alpha with placebo or no treatment after tumor resection or ablation

6

0

Zhao

Journal of Interventional Radiology (China) (2013)

China

Unselected HCC

21/2339

RFA + TACE vs RFA or TACE alone

21

0

Zhao

Zhonghua Wai Ke Za Zhi (2008)

China

Unselected HCC

9/494

Preoperative portal vein embolization (PVE) vs no PVE for extended hepatectomy

0

9

Zheng

Transplantation (2014)

China

Unselected HCC

62/10170

LT vs resection

0

62

Zheng

Int J Cancer (2014)

China

Unselected HCC

48/4747

Hepatectomy + adjuvant chemotherapy vs hepatectomy alone

13

35

Zhong

Hepatol Res (2010)

China

UICC TNM stage 3A HCC

6/659

Postoperative adjuvant TACE

6

0

Zhong

World Chinese Journal of Digestology (2012); PLoS One (2013)

China

Post-operative HCC

6/930

Curative treatments alone vs curative treatments + oral vitamin K2 analogs

6

0

Zhong

Molecular and Clinical Oncology (2014)

China

Post-operative HCC

3/286

Adjuvant conventional oral systemic chemotherapy after curative hepatic resection

3

0

Zhou

Dig Dis Sci (2011)

China

Unselected HCC

10/494

Laparoscopic vs open resection

0

10

Zhou

Langenbecks Arch Surg (2011)

China

Unselected HCC

16/2917

Anatomic vs nonanatomic resection

0

16

Zhou

BMC Gastroenterol (2013)

China

Unselected HCC

21/3210

Preoperative TACE vs no preoperative TACE

4

17

Zhou

Zhonghua Wai Ke Za Zhi (2011)

China

Small HCC (Milan criteria)

4/539

RFA vs surgical resection

4

0

Zhou

BMC Gastroenterol (2010)

China

Small HCC (Yao’s criteria)

10/1411

RFA vs surgical resection

1

9

Zhou

World J Surg (2014)

China

Unselected HCC

20/8204

Antiviral therapy after curative resection

1

19

Zhu

Transplant Proc (2013)

China

Unselected HCC

14/1508

Primary LT vs salvage LT

0

14

Zhuang

PLoS One (2013)

China

Unselected HCC

13/1344

Interferon after curative therapy

13

0

Zhuang

Zhonghua Gan Zang Bing Za Zhi (2012)

China

Unselected HCC

8/857

Interferon after curative therapy

8

0

Zou

Acta Academiae Medicinae Sinicae (2011)

China

Advanced HCC

2/828

Sorafenib vs placebo

2

0

Table 2: Findings of meta-analyses: An overview of included studies regarding LT

First author

Journal (Year)

Comparisons

OS

DFS, RFS, TTP, PFS

Recurrence, time to recurrence

Other endpoints

Major comments

Living donor LT (LDLT) versus deceased donor LT (DDLT)

Al Hasan

Liver Transpl (2014)

LDLT vs DDLT

OS: 1-, 3-, 5-year: statistically similar.

DFS: 1-, 3-, 5-year: statistically similar.

Recurrence: 1-, 3-year: statistically similar. 5-year: favor DDLT.

NA.

OS and DFS are comparable, but long-term recurrence is higher in LDLT.

Grant

Clin Transplant (2013)

LDLT vs DDLT

OS: statistically similar.

DFS: favor DDLT.

NA.

NA.

LDLT has lower DFS than DDLT.

Liang

Liver Transpl (2012)

LDLT vs DDLT

OS: 1-, 3-, 5-year: statistically similar.

RFS: 1-, 3-, 5-year: statistically similar.

Recurrence: statistically similar.

NA.

LDLT is an acceptable option especially for patients within Milan criteria.

Primary LT versus salvage LT

Li

World J Gastroenterol (2012)

Primary LT vs salvage LT

OS: 1-, 3-, 5-year: statistically similar.

DFS: 1-, 3-, 5-year: statistically similar.

NA.

NA.

OS and DFS were not significantly different.

Zhu

Transplant Proc (2013)

Primary LT vs salvage LT

OS: 1-, 3-, 5-year: statistically similar.

DFS: 1-, 3-year: statistically similar. 5-year: favor primary LT.

NA.

Operative time: longer in salvage LT. Intraoperative blood loss: increased in salvage LT. Number of transfused units of packed red blood cells: larger in salvage LT. Length of hospital stay and ICU stay: statistically similar. Peri-operative mortality: statistically similar.

Salvage LT achieves the same short- and long-term outcomes as primary LT.

Sirolimus-based immunosuppression (SRL) after LT

Liang

Liver Transpl (2012)

SRL after LT vs SRL-free

OS: 1-, 3-, 5-year: favor SRL.

DFS: 1-year: favor SRL.

Recurrence: 1-year: favor SRL.

Major SRL-related post-transplant complications: statistically similar.

SRL is safe and prolongs survival and decrease tumor recurrence.

Menon

Aliment Pharmacol Ther (2013)

SRL after LT vs SRL-free

Overall mortality: favor SRL.

RFS: better in SRL (no statistical comparison). Recurrence-related mortality: low in SRL.

Recurrence: favor SRL.

NA.

SRL has lower recurrence rate, lower overall mortality and longer RFS and OS.

LT versus surgical resection

Dhir

HPB (2012)

LT vs resection

OS: 5-year: early HCC: favor LT. early HCC with well compensated cirrhosis: favor LT. early HCC using ITT strategy: statistically similar. early HCC with well compensated cirrhosis using ITT strategy: favor LT.

NA.

NA.

NA.

LT has favorable survival advantage in some settings.

Hoshida

Hepatology (2000)

Surgical resection vs PEI and LT (including LT vs surgical resection)

OS: Surgical resection vs LT: 3-year: statistically similar.

DFS: Surgical resection vs LT: 3-year: favor LT.

NA.

NA.

LT improved 3-year DFS for HCC patients.

Proneth

Ann Surg Oncol (2014)

LT vs resection

OS: 5-year: statistically similar.

NA.

NA.

NA.

LR is a good alternative to LT in patients with resectable HCC in whom both seem feasible.

Rahman

J Gastrointest Surg (2012)

LT vs resection

OS: 1-year: all studies: favor resection. non-ITT analysis: statistically similar. ITT analysis: favor resection. 5-year: all studies: statistically similar. non-ITT analysis: statistically similar. ITT analysis: favor LT. 10-year: all studies: favor LT. non-ITT analysis: favor LT. ITT analysis: favor LT.

DFS: 1-year: all studies: statistically similar. non-ITT analysis: statistically similar. ITT analysis: statistically similar. 5-year survival: all studies: favor LT. non-ITT analysis: favor LT. ITT analysis: favor LT. 10-year: all studies: favor LT. non-ITT analysis: favor LT. ITT analysis: statistically similar.

NA.

NA.

LT results in increased DFS and OS.

Xu

Journal of Xi’an Jiaotong University (2012)

LT vs resection

OS: 1-year: statistically similar. 3-, 5-year survival: favor LT.

DFS: 5-year: favor LT.

Recurrence: favor LT.

NA.

Both treatments were effective. But LT has a better prognosis than resection.

Xu

Hepatobiliary Pancreat Dis Int (2014)

LT vs resection

OS: 1-, 3-year: statistically similar. 5-year survival: favor LT.

DFS: 1-, 3-, 5-year: favor LT.

NA.

Surgery-related morbidity: higher in LT. Surgery-related mortality: higher in LT.

Long-term survival and tumor-free survival are higher in LT than in resection.

Zheng

Transplantation (2014)

LT vs resection

OS: 1-year: statistically similar. 3-, 5-year: favor LT.

DFS: 1-, 3-, 5-year: favor LT.

Recurrence: favor LT.

NA.

LT provides increased survival and lower recurrence rates than resection.

Table 3: Findings of meta-analyses: An overview of included studies regarding surgical resection

Table 4: Findings of meta-analyses: An overview of included studies regarding ablation therapy

Table 5: Findings of meta-analyses: An overview of included studies regarding TACE

LT

Living donor LT (LDLT) versus deceased donor LT (DDLT)

Three meta-analyses compared the outcomes of LDLT versus DDLT [8, 41, 67]. All of them demonstrated that the OS was statistically similar between the two groups [8, 41, 67]. Two of them showed that the 1-, 3-, and 5-year DFS were statistically similar between the two groups [8, 67], but another one favored DDLT in term of DFS [41]. One of them found that the recurrence was statistically similar between the two groups [67]; by comparison, another one favored LDLT in term of 5-year recurrence, but not 1- or 3-year recurrence [8].

Only non-RCT studies, rather than RCTs, were included in the three meta-analyses.

The meta-analysis by Grant had a larger number of included studies than those by Al Hasan and Liang (16 versus 7 and 7) (Supplementary Table S9). Notably, there was an overlap of included studies between the two meta-analyses by Liang and Grant. All studies which were included in the meta-analysis by Liang were also covered by the meta-analysis by Grant. The meta-analysis by Al Hasan did not show the included studies.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Grant might be more reliable. In details, LDLT has lower DFS than DDLT.

Primary versus salvage LT

Two meta-analyses compared the outcomes of primary versus salvage LT [59, 157]. Both of them demonstrated that the OS and 1- and 3-year DFS were statistically similar between the two groups [59, 157]. One of them favored primary LT in term of 5-year DFS [157]; by comparison, another one showed that the 5-year DFS was statistically similar between the two groups [59]. In addition, salvage LT had significantly longer operative time, increased intra-operative blood loss, and larger number of transfused units of packed red blood cells than primary LT [157]. But the length of hospital and ICU stay was statistically similar between the two groups [157].

Only non-RCT studies, rather than RCTs, were included in the two meta-analyses.

The meta-analysis by Zhu had a larger number of included studies than that by Li (14 versus 11) (Supplementary Table S10). Notably, there was an overlap of included studies between them. All studies which were included in the meta-analysis by Li were also included in the meta-analysis by Zhu.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Zhu might be more reliable. In details, salvage LT achieves the same short- and long-term survival as primary LT. However, primary LT was significantly superior to salvage LT in terms of operative time, blood loss, and blood transfusion.

Sirolimus-based immunosuppression after LT

Two meta-analyses compared the outcomes of sirolimus-based immunosuppression versus no sirolimus after LT [66, 83]. Both of them favored the use of sirolimus after LT in terms of OS, DFS/RFS, and recurrence [66, 83].

Only non-RCT studies, rather than RCTs, were included in the two meta-analyses.

Both of them had a similar number of included studies (5 versus 5) (Supplementary Table S11). But not all included studies were the same between them.

The results were completely consistent between the two meta-analyses. In details, the use of sirolimus after LT should be favored.

LT versus surgical resection

Seven meta-analyses compared the outcomes of LT versus surgical resection [25, 46, 96, 98, 129, 131, 146]. There were 4, 4, 6, and 1 meta-analyses to compare the 1-, 3-, 5-, and 10-year survival, respectively. As for the 1-year survival, three of them demonstrated that the survival was statistically similar between the two groups [129, 131, 146], but another one favored surgical resection [98]. As for the 3-year survival, two of them found that the survival was statistically similar between the two groups [46, 131], but another two favored LT [129, 146]. As for the 5-year survival, two of them showed that the survival was statistically similar between the two groups [96, 98], but another four favored LT [25, 129, 131, 146]. As for the 10-year survival, the only one meta-analysis favored LT [98]. There were 3, 3, 4, and 1 meta-analyses to compare the 1-, 3-, 5-, and 10-year DFS, respectively. As for the 1-year DFS, two of them favored LT [131, 146], but another one found that the 1-year DFS was statistically similar between the two groups [98]. As for the 3-year DFS, all of them favored LT [46, 131, 146]. As for the 5-year DFS, all of them favored LT [98, 129, 131, 146]. As for the 10-year DFS, the only one meta-analysis favored LT [98]. Two meta-analyses compared the recurrence. Both of them favored LT in term of recurrence [129, 146].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analysis by Zhang had the largest number of included studies (n = 62) (Supplementary Table S12). By comparison, the number of included studies was less than 20 in 6 other meta-analyses.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Zhang might be more reliable. In details, LT provides a significantly better survival and a lower recurrence.

Surgical resection

Surgical resection margin 1 cm versus 2 cm

Only one meta-analysis compared the outcomes of hepatectomy with a margin aiming at 2 cm versus those with a margin aiming at 1 cm [109]. Regardless of study design, the 1-year survival was statistically similar between the two groups [109]. In the subgroup analysis of randomized studies, the 3- and 5-year survival and DFS were better in patients undergoing hepatectomy with a margin aiming at 2 cm than in those with a margin aiming at 1 cm [109]. Contrarily, in the subgroup analysis of non-randomized studies, the 3- and 5-year survival and DFS were statistically similar between the two groups [109].

One RCT and 4 non-RCT studies were included in this meta-analysis.

Laparoscopic versus open resection

Nine meta-analyses compared the outcomes of laparoscopic versus open resection [30, 62, 9495, 111, 126, 135, 137, 156]. All of them demonstrated that the OS and DFS/RFS at any time points were statistically similar between the two groups [30, 62, 9495, 111, 126, 135, 137, 156]. Two of them also found that the recurrence was statistically similar between the two groups [62, 126]. Eight of them demonstrated statistically similar operative time between the two groups [30, 62, 95, 111, 126, 135, 137, 156], but one demonstrated significantly longer operative time in laparoscopic resection group [94]. All of them demonstrated that blood loss or intraoperative bleeding was significantly less in laparoscopic resection group [30, 62, 9495, 111, 126, 135, 137, 156]. Among the 7 meta-analyses evaluating the blood transfusion, 6 demonstrated significantly less blood transfusion in laparoscopic resection group [30, 62, 111, 126, 137, 156], and one demonstrated statistically similar blood transfusion between the two groups [94]. Among the 6 meta-analyses evaluating the overall complications, 5 demonstrated significantly less complications in laparoscopic resection group [30, 62, 94, 111, 135], and one demonstrated statistically similar complications between the two groups [126]. Among the 8 meta-analyses evaluating the hospital length, all demonstrated significantly shorter hospital study in laparoscopic resection group [30, 62, 94, 111, 126, 135, 137, 156].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analyses by Park, Xiong, and Yin had the largest number of included studies (n = 15) followed by the meta-analyses by Yao (n = 13), Zhou (n = 10), Li (n = 10), Fancellu (n = 9), Pang (n = 7), and Twaij (n = 4) (Supplementary Table S13). The included studies were completely same between the two meta-analyses by Xiong and Yin. However, the studies included in the meta-analysis by Park were different from those included in the meta-analyses by Xiong and Yin.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analyses by Park, Xiong, and Yin might be more reliable. In details, they suggested that the operative time was statistically similar between the two groups and that laparoscopic resection was superior to open resection in terms of blood loss, blood transfusion, complications, and hospital stay.

Anatomic resection versus non-anatomic resection

Six meta-analyses compared the outcomes of anatomic versus non-anatomic resection [15, 23, 60, 110, 136, 152]. Four of them demonstrated that the OS was statistically similar between the two groups [15, 60, 110, 136], but another two favored anatomic resection in term of 5-year survival [23, 152]. One of them found that the DFS was statistically similar between the two groups [60], but another four favored anatomic resection in term of DFS [15, 23, 136, 152]. Two of them showed that the recurrence was statistically similar between the two groups [15, 110], but another two favored anatomic resection in term of local intrahepatic recurrence [136, 152]. Post-operative complications were statistically similar between the two groups [23, 110, 136, 152].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analysis by Cucchetti had the largest number of included studies (n = 18) followed by the meta-analyses by Zhou (n = 16), Tang (n = 12), Ye (n = 11), Chen (n = 9), and Li (n = 4) (Supplementary Table S14).

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Zhang might be more reliable. In details, anatomic resection was superior to non-anatomic resection in terms of OS and DFS.

Surgical resection + I131 lipiodol versus surgical resection alone

Two meta-analyses compared the outcomes of surgical resection in combination with I131 lipiodol versus surgical resection alone [36, 40]. Both of them favored the combination therapy in terms of OS, DFS, and recurrence [36, 40].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analysis by Gong had a larger number of included studies than that by Furtado (10 versus 5) (Supplementary Table S15). Notably, there was an overlap of included studies between them. All studies which were included in the meta-analysis by Furtado were also included in the meta-analysis by Gong.

The results were completely consistent between the two meta-analyses. In details, surgical resection in combination with I131 lipiodol should be favored.

Surgical resection + TACE versus surgical resection alone

Pre-operative TACE

Four meta-analyses compared the outcomes of surgical resection in combination with pre-operative TACE versus surgical resection alone [17, 116, 138, 153]. All of them found that the OS, DFS, and recurrence were statistically similar between the two groups [17, 116, 138, 153].

RCT studies were included in the meta-analyses by Cheng (n = 4), Wang (n = 3), and Zhou (n = 4), but not in the meta-analysis by Yu (n = 0).

The meta-analysis by Zhou had the largest number of included studies (n = 21) followed by the meta-analyses by Yu (n = 7), Cheng (n = 4), and Wang (n = 3) (Supplementary Table S16). All studies which were included in the two meta-analyses by Cheng and Wang were also included in the meta-analysis by Zhou.

The results were completely consistent between the two meta-analyses. In details, pre-operative TACE did not improve the OS or DFS.

Post-operative TACE

Two meta-analyses compared the outcomes of surgical resection in combination with post-operative TACE versus surgical resection alone [17, 149]. Both of them favored post-operative TACE in terms of OS, DFS, and recurrence [17, 149].

Only RCT studies were included in the two meta-analyses.

Although the number of included studies was the same between the two meta-analysis by Cheng and Zhong (n = 6) (Supplementary Table S17), not all included studies were the same between them.

The results were completely consistent between the two meta-analyses. In details, post-operative TACE should be favored.

Surgical resection + adjuvant chemotherapy versus surgical resection alone

Five meta-analyses compared the outcomes of surgical resection in combination with adjuvant chemotherapy versus surgical resection alone [78, 92, 112, 147148].

Oral systemic chemotherapy

Oral systemic chemotherapy was evaluated in two meta-analyses [78, 148]. The OS, RFS, and recurrence were statistically similar between patients with and without chemotherapy [78, 148].

RCT studies were included in the meta-analyses by Zhong (n = 3) and Mathurin (n = 1).

The meta-analysis by Zhong had a larger number of included studies than that by Mathurin (3 versus 2) (Supplementary Table S18). Not all included studies were the same between them.

The results were completely consistent between the two meta-analyses. In details, the adjunctive use of oral systemic chemotherapy should not be favored in patients undergoing surgical resection.

Transarterial chemotherapy

Transarterial chemotherapy was evaluated in one meta-analysis [78]. As for the pre-operative transarterial chemotherapy, the overall analysis of both RCTs and non-RCTs demonstrated that chemotherapy improved the 2-year survival, but not the 1- or 3-year survival. The subgroup analysis of RCTs showed that the 1-, 2-, and 3-year recurrence were statistically similar between the two groups. As for the post-operative transarterial chemotherapy, the overall analysis of both RCTs and non-RCTs demonstrated that chemotherapy improved the 1-, 2-, and 3-year survival. The subgroup analysis of RCTs showed that chemotherapy improved the 2- and 3-year survival, but not the 1-year survival.

Approaches of chemotherapy were mixed in three meta-analyses [92, 112, 147]. The statistical results were largely inconsistent among them. One of them favored the chemotherapy in term of OS [147]; one showed that the OS was statistically similar between the two groups [112]; one demonstrated that the OS was decreased by chemotherapy [92].

RCT studies were included in the meta-analyses by Zheng (n = 13), Wang (n = 8), and Ono (n = 3).

The meta-analysis by Zheng had a larger number of included studies than those by Wang and Ono (48 versus 8 and 3) (Supplementary Table S19).

Given its superiority in the quantity of RCT studies, the results of the meta-analysis by Zheng might be more reliable.

Surgical resection + immunotherapy versus surgical resection alone

Four meta-analyses compared the outcomes of surgical resection in combination with immunotherapy versus surgical resection alone [32, 75, 112, 124]. All of them demonstrated that the OS was statistically similar between the two groups [32, 75, 112, 124]. One of them favored the combination therapy in term of RFS. One of them favored the combination therapy in terms of 1- and 3-year recurrence [124]; one favored the combination therapy in term of 1-year recurrence, but not 3-year recurrence [75]; one showed that the recurrence was statistically similar between the two groups [32].

Only RCT studies were included in the meta-analyses by Xie (n = 6), Ma (n = 4), Wang (n = 3), and Flores (n = 2).

The meta-analysis by Xie had the largest number of included studies followed by those by Ma, Wang, and Flores (6 versus 4, 3, and 2) (Supplementary Table S20). Notably, there was an overlap of included studies among them.

Given its superiority in the quantity of RCT studies, the results of the meta-analysis by Xie might be more reliable. In details, the adjunctive use of immunotherapy might not be favored in patients undergoing surgical resection.

Surgical resection + PVE versus surgical resection alone

One meta-analysis compared the outcomes of surgical resection in combination with PVE versus surgical resection alone [145]. The 1-, 3-, and 5-year survival and intrahepatic and distant recurrence were statistically similar between the two groups [145].

Only non-RCT studies were included in the meta-analysis by Zhao.

Ablation therapy

RFA versus surgical resection

Eighteen meta-analyses compared the outcomes of RFA versus surgical resection [11, 16, 24, 27, 31, 33, 47, 61, 69, 72, 89, 97, 106, 117, 119, 127, 151, 153]. As for the OS, seven of them favored surgical resection [27, 31, 47, 61, 97, 106, 127]; four demonstrated that the OS was statistically similar between the two groups [11, 16, 119, 151]; four showed that the 1-year survival was statistically similar between the two groups, but the 5-year survival was better in surgical resection group [33, 72, 89, 117]; one found that the 1- and 5-year survival were statistically similar between the two groups, but the 3-year survival was better in surgical resection group [155]; one reported that surgical resection had better OS than RFA in the subgroup analyses of a single nodule 3–5 cm and ≤ 3 cm, but the OS was statistically similar between the two groups in the subgroup analyses of a single nodule < 2 cm and 2–3 nodules < 3 cm [24].

As for the DFS, nine of them favored surgical resection in terms of DFS/RFS at any time points [11, 27, 31, 61, 72, 89, 97, 106, 155]; three showed that the 1-year DFS was statistically similar between the two groups, but the 3- and/or 5-year DFS were better in surgical resection group than in RFA group [16, 33, 151]; one reported that surgical resection had better DFS than RFA in the subgroup analyses of a single nodule 3–5 cm and ≤ 3 cm, but the DFS was statistically similar between the two groups in the subgroup analyses of a single nodule < 2 cm and 2–3 nodules < 3 cm [24].

As for the recurrence, three of them favored surgical resection [11, 47, 61]; two favored RFA [127, 151]; one found that the recurrence was statistically similar between the two groups [24]; three showed that the 1-year recurrence was statistically similar between the two groups, but the 3-year recurrence was less in surgical resection group than in RFA group [31, 33, 117]; one reported that the 1- and 3-year recurrence were statistically similar between the two groups, but the recurrence at the end of follow-up was less in RFA group than in surgical resection group [69]; one demonstrated that the distant intrahepatic recurrence was statistically similar between the two groups, but the local intrahepatic recurrence was less in surgical resection group than in RFA group [153]; one favored surgical resection in term of recurrence at previous sites, but favored RFA in term of recurrence at new sites [72].

According to the description of each meta-analysis, RCT studies were included the meta-analyses by Liu (Surg Laparosc Endosc Percutan Tech, 2010) (n = 8), Ni (n = 6), Fu (n = 5), Zhou (Zhonghua Wai Ke Za Zhi, 2011) (n = 4), Hu (n = 4), Feng (n = 3), Qi (n = 3), Wang (n = 3), Weis (n = 3), Duan (n = 2), Li (n = 2), Sun (n = 2), Xu (n = 2), Chen (n = 1), and Zhou (BMC Gastroenterol, 2010) (n = 1). The information regarding the inclusion of RCT studies was not available in the meta-analyses by Cai and Cucchetti. After checking the relevant information, we confirmed the following: 1) in the meta-analysis by Liu (Surg Laparosc Endosc Percutan Tech, 2010), all included studies were non-RCTs; 2) in the meta-analysis by Ni, there were one RCT regarding resection v.s. PEI, one RCT regarding resection v.s. PEI or microwave ablation, and two RCTs with overlapped data; 3) in the meta-analysis by Fu, there were one RCT regarding comparison of resection v.s. PEI or microwave ablation and two RCTs with overlapped data; 4) in the meta-analysis by Zhou (Zhonghua Wai Ke Za Zhi, 2011), one included study was non-RCT; and 5) because no included studies were listed in the meta-analysis by Hu, we could not check the accuracy. Thus, the largest number of RCT studies included in the meta-analyses should be 3.

The meta-analysis by Wang had the largest number of included studies (n = 28) followed by the meta-analyses by Feng (n = 23), Hu (n = 18), Cucchetti (n = 17), Xu (n = 13), Duan (n = 12), Sun (n = 11), Zhou (BMC Gastroenterol, 2010) (n = 10), Ni (n = 10), Liu (World J Gastroenterol, 2010) (n = 10), Liu (Surg Laparosc Endosc Percutan Tech, 2010) (n = 8), Li (n = 6), Chen (n = 6), Fu (n = 5), Cai (n = 5), Zhou (Zhonghua Wai Ke Za Zhi, 2011) (n = 4), Weis (n = 3), and Qi (n = 3) (Supplementary Table S21).

Given the superiority in the quantity of RCT studies, the meta-analyses by Feng, Qi, Wang, and Weis might be more reliable. In details, surgical resection should be superior to RFA for the improvement of OS.

PEI versus surgical resection

Two meta-analyses compared the outcomes of PEI versus surgical resection [46, 100]. Both of them demonstrated that OS and RFS were statistically similar between the two groups [46, 100].

Only one RCT study was included in the meta-analysis by Schoppmeyer.

The meta-analysis by Hoshida had a larger number of included studies than that by Schoppmeyer (5 versus 1) (Supplementary Table S22). However, no included studies were overlapped between them.

The results were completely consistent between the two meta-analyses. In details, PEI was similar to surgical resection in terms of OS and RFS.

Non-surgical-resection ablation versus surgical resection

One meta-analysis compared the outcomes of non-surgical-resection ablation versus surgical resection [26]. The 1- and 3-year survival and DFS were statistically similar between the two groups [26].

RFA versus PEI or PAI

Eight meta-analyses compared the outcomes of RFA versus PEI or PAI [9, 20, 26, 38, 93, 102, 119, 130]. All of them favored RFA over PEI in terms of OS, DFS, and/or recurrence [9, 20, 26, 38, 93, 102, 119, 130]. Additionally, one of them found that the OS, local recurrence, de novo tumor, and adverse event were statistically similar between RFA and PAI groups [38].

RCT studies were included in the meta-analyses by Bouza (n = 6), Weis (n = 6), Xu (n = 6), Dong (n = 5), Germani (n = 5), Orlando (n = 5), Cho (n = 4), and Shen (n = 4).

The meta-analyses by Bouza, Weis, and Xu had the largest number of included studies (n = 6) followed by the meta-analyses by Dong (n = 5), Germani (n = 5), Orlando (n = 5), Shen (n = 5), and Cho (n = 4) (Supplementary Table S23).

The results regarding the comparison between RFA v.s. PEI were completely consistent among meta-analyses. In details, RFA should be superior to PEI for the improvement of OS and DFS.

RFA versus cryosurgery ablation

One meta-analysis compared the outcomes of RFA versus cryosurgery ablation [51]. Although the OS was statistically similar between the two groups, RFA had less recurrence and complications than cryosurgery ablation [51].

RFA versus other therapeutic methods

One meta-analysis compared the outcomes of RFA versus any other therapeutic methods [50]. RFA was superior to other treatment methods for early HCC in terms of local recurrence and 3-year survival [50]. However, no subgroup analysis was performed according to the different treatment modalities.

Additionally, one meta-analysis compared the outcomes of RFA versus microwave or laser ablation [119]. However, only one trial was identified for each comparison.

PEI versus PAI

Two meta-analyses compared the outcomes of PEI versus PAI [38, 100]. Both of them showed that the OS, RFS, and recurrence were statistically similar between the two groups [38, 100].

RCT studies were included in the meta-analyses by Germani (n = 2) and Schoppmeyer (n = 2).

Both of them had a similar number of included studies (n = 2) (Supplementary Table S24). However, not all of the included studies were identical.

The results were completely consistent between the two meta-analyses. In details, PEI was similar to PAI in terms of OS and RFS.

RFA + TACE versus mono-therapy

Eleven meta-analyses compared the outcomes of RFA in combination with TACE versus RFA or TACE alone [26, 45, 53, 55, 68, 71, 74, 8788, 133, 144]. Seven of them favored the combination therapy in term of OS [45, 53, 55, 71, 88, 133, 144]; two favored the combination therapy in terms of 1- and 3-year survival, but not 5-year survival [74, 87]; one favored the combination therapy in term of 5-year survival, but not 1- or 3-year survival [26]; one found that the 1-year survival was statistically similar between the two groups [68].

Three meta-analyses compared the RFS of RFA in combination with TACE versus RFA or TACE alone [71, 8788]. As for the 1-year RFS, one meta-analysis favored the combination therapy [71], but another two showed that the 1-year RFS was statistically similar between the two groups [8788]. By comparison, all of them favored the combination therapy in term of 3-year RFS [71, 8788].

RCT studies were included in the meta-analyses by Zhao (n = 21), Jiang (n = 8), Kong (n = 8), Ni (World J Gastroenterol, 2013) (n = 8), Yan (n = 8), Liu (n = 7), Lu (n = 7), Ni (J Cancer Res Clin Oncol, 2013) (n = 6), and Liao (n = 1), but not in the meta-analyses by Dong and Han.

The meta-analysis by Zhao had the largest number of included studies (n = 21), followed by those by Jiang (n = 19), Kong (n = 19), Yan (n = 19), Yan (n = 18), Han (n = 8), Ni (World J Gastroenterol, 2013) (n = 8), Liu (n = 7), Lu (n = 7), Ni (J Cancer Res Clin Oncol, 2013) (n = 6), Dong (n = 5), and Liao (n = 1) (Supplementary Table S25). Notably, all of the 19 included studies were completely identical among the three meta-analyses by Jiang, Kong, and Yan.

Given the superiority in the number of RCTs, the meta-analyses by Zhao, Jiang, Kong, Ni, and Yan should be more reliable. In details, RFA in combination with TACE should be favored in term of OS.

PEI + TACE versus mono-therapy

Three meta-analyses compared the outcomes of PEI in combination with TACE versus PEI or TACE alone [68, 114115]. Two of them favored the combination therapy in term of OS [114115]. Another one meta-analysis was performed according to the study design. In the subgroup analysis of RCTs, the combination therapy significantly improved the 3-year survival, rather than 1-year survival. By contrast, in the subgroup analysis of observational studies, the combination therapy significantly improved the 1-year survival, rather than 3-year survival [68].

RCT studies were included in all of the 3 meta-analyses by Wang N (Med Oncol, 2011) (n = 7), Wang W (Liver Int, 2010) (n = 6), and Liao (PLoS One, 2013) (n = 4).

The meta-analysis by Wang N (Med Oncol, 2011) had a larger number of included studies than those by Wang W (Liver Int, 2010) and Liao (7 versus 6 and 4) (Supplementary Table S26). However, not all studies included by Wang W and Liao were included by Wang N.

Given the superiority in the number of RCTs, the meta-analysis by Wang N (Med Oncol, 2011) might be more reliable. In details, PEI in combination with TACE should be favored in term of OS.

Any ablation therapy + TACE versus mono-therapy

Two meta-analyses compared the outcomes of unclassified ablation therapies in combination with TACE versus mono-therapy [42, 115]. Both of them favored the combination therapy in terms of OS, recurrence, and tumor response [42, 115].

RCT studies were included in the meta-analyses by Wang (n = 10) and Gu (n = 7).

The meta-analysis by Gu had a larger number of included studies than that by Wang (18 versus 10) (Supplementary Table S27). However, not all studies included by Wang were included by Gu.

The results were completely consistent between the two meta-analyses. In details, TACE in combination with ablation therapy was favored.

TACE

TACE/TAE versus no active treatment

Seven meta-analyses compared the outcomes of TACE/TAE versus no active treatment or supportive care [12, 39, 57, 73, 77, 91, 132]. Two of them showed that the OS was statistically similar between the two groups [39, 91]; another five favored TACE/TAE in term of OS [12, 57, 73, 77, 132].

RCT studies were included in the meta-analyses by Marelli (n = 9), Oliveri (n = 8), Llovet (n = 7), Camma (n = 5), Geschwind (n = 4), and Leng (n = 2), but not in the meta-analysis by Xue.

The meta-analysis by Marelli had the largest number of included studies (n = 9) followed by those by Oliveri (n = 8), Xue (n = 8), Llovet (n = 7), Camma (n = 5), Geschwind (n = 4), and Leng (n = 3) (Supplementary Table S28). However, not all included studies were completely overlapped among them.

Given the superiority in the number of RCTs, the meta-analysis by Marelli might be more reliable. In details, TACE/TAE should be favored.

TACE versus TAE

Three meta-analyses compared the outcomes of TACE versus TAE [12, 77, 125]. All of them showed that the OS was statistically similar between the two groups [12, 77, 125].

Only RCT studies were included in the meta-analyses by Xie (n = 5), Marelli (n = 3), and Camma (n = 2).

The meta-analysis by Xie had a larger number of included studies than those by Marelli and Camma (5 versus 3 and 2) (Supplementary Table S29). However, not all included studies were completely overlapped among them.

The results were completely consistent among them. In details, TACE was similar to TAE in term of OS.

Drug-eluting bead (DEB)-TACE versus conventional TACE (cTACE)

Three meta-analyses compared the outcomes of DEB-TACE versus cTACE [37, 44, 48]. One of them evaluated the OS [48]. DEB-TACE was significantly better than cTACE in terms of 1- and 2-year survival. But the 6-month and 3-year survival were statistically similar between the two groups.

Two of them demonstrated that tumor response or disease control rate was statistically similar between them. Another one meta-analysis demonstrated that tumor response rate was significantly higher in DEB-TACE group than in cTACE group.

Two of them evaluated the complications [37, 44]. The incidence of complications was statistically similar between the two groups.

RCT studies were included in the meta-analyses by Han (n = 3) and Huang (n = 2), but not in the meta-analysis by Gao.

The meta-analysis by Huang had a larger number of included studies than those by Han and Gao (7 versus 5 and 2) (Supplementary Table S30). However, not all included studies were completely overlapped among them.

Given the superiority in the number of RCTs, the meta-analysis by Han might be more reliable. In details, DEB-TACE was similar to cTACE in the term of tumor response.

TACE versus microsphere embolization

One meta-analysis compared the outcomes of TACE versus microsphere embolization [123]. Microsphere embolization was superior to TACE in terms of OS, TTP, and tumor response [123]. In the subgroup analyses, the benefit was statistically significant in patients undergoing 32P glass microspheres, but not in those undergoing 90Y microspheres.

RCT studies were included in the meta-analysis by Xie (n = 7).

TACE + sorafenib versus TACE

Four meta-analyses compared the outcomes of TACE in combination with sorafenib versus TACE alone [35, 70, 134, 140]. Three of them favored the combination therapy in term of OS [35, 134, 140], but another one found that the OS was statistically similar between the two groups [70]. The survival benefit of the combination therapy was statistically significant in the subgroup analysis of retrospective studies, but not in that of RCTs [134].

RCT studies were included in the meta-analyses by Liu (n = 3), Yang (n = 3), and Zhang (n = 2), but not in the meta-analysis by Fu.

The meta-analysis by Fu had the largest number of included studies (n = 9), followed by those by Liu (n = 7), Yang (n = 6), and Zhang (n = 6) (Supplementary Table S31). However, not all included studies were completely overlapped among the 4 meta-analyses.

Given the superiority in the number of RCTs, the meta-analysis by Liu and Yang might be more reliable. In details, TACE plus sorafenib was not favored in term of OS.

TACE + high-intensity focused ultrasound (HIFU) versus TACE

Two meta-analyses compared the outcomes of TACE in combination with HIFU versus TACE alone [13, 68]. One of them demonstrated that both OS and tumor response were improved by the combination therapy [13]. Another one meta-analysis was performed according to the study design [68]. In the subgroup analysis of observational studies, both 1- and 3-year survival were significantly improved by the combination therapy [68]. By comparison, in the subgroup analysis of RCTs, only 1-year survival, rather than 3-year survival, was significantly improved by the combination therapy [68].

RCT study was included in the meta-analysis by Liao (n = 1), but not in the meta-analysis by Cao.

The meta-analysis by Cao had a larger number of included studies than that by Liao (9 versus 5) (Supplementary Table S32). All studies which were included in the meta-analysis by Liao were also included in the meta-analysis by Cao.

Given the superiority in the number of RCTs, the meta-analysis by Liao might be more reliable. In details, TACE plus HIFU should be favored in term of 1-year survival, but not 3-year survival.

TACE + thermotherapy versus TACE

Only one meta-analysis compared the outcomes of TACE in combination with thermotherapy versus TACE alone [64]. Both 1- and 2-year survival were significantly improved by the combination therapy, but the 0.5-, 1.5-, and 3-year survival were statistically similar between the two groups [64]. Additionally, the overall effective rate and quality of life were improved by the combination therapy [64].

TACE + AHCS versus TACE or AHCS

Only one meta-analysis compared the outcomes of TACE in combination with AHCS versus TACE or AHCS alone [65]. Compared with TACE alone, the combination therapy had significantly better 0.5-, 1-, 1.5-, 2-, and 2.5-year survival, but the 3-year survival was statistically similar between the two groups [65]. Compared with AHCS alone, the combination therapy had significantly better 0.5-, 1.5-, 2-, and 2.5-year survival, but similar 1- and 3-year survival [65]. Additionally, the combination therapy was superior to the mono-therapy in terms of total effective rate, complete necrosis rate, recurrence, AFP reduction, and CD4 improvement.

TACE + radiotherapy versus TACE alone

Two meta-analyses compared the outcomes of TACE in combination with radiotherapy versus TACE alone [68, 80]. Both of them demonstrated that the combination therapy had significantly better 1-, 2-, 3-, and 5-year survival than TACE alone [68, 80]. Additionally, one of them showed that the combination therapy significantly increased the tumor response, but did not influence the development of adverse events, such as nausea/vomit, leukocyte count declined, alanine aminotransferase level increased, and total bilirubin level increased [80].

RCT studies were included in the meta-analyses by Meng (n = 5) and Liao (n = 3).

The meta-analysis by Meng had a larger number of included studies than that by Liao (17 versus 7) (Supplementary Table S33). All studies which were included in the meta-analysis by Liao were also included in the meta-analysis by Meng.

The results regarding the OS were completely consistent among them. In details, TACE plus radiotherapy should be favored in term of OS.

TACE + 3D-CRT versus TACE alone

Only one meta-analysis compared the outcomes of TACE in combination with 3D-CRT versus TACE alone [68]. Regardless of study design, the combination therapy was superior to TACE alone in terms of 1- and 3-year survival [68].

Only one RCT study was included in the meta-analysis by Liao.

TACE + TCMs versus TACE alone

Six meta-analyses compared the outcomes of TACE in combination with TCMs versus TACE alone [1819, 79, 81, 108, 122]. Three of them favored the combination therapy in term of OS [18, 79, 108]; one favored the combination therapy in terms of 1-, 2-, and 3-year survival, but not 6-month survival [19]; one favored the combination therapy in term of 2-year survival, but not 1-year survival [122]; one did not report the survival data [81].

Five of them favored the combination therapy in term of tumor response [1819, 79, 81, 122]. Another one did not report the relevant data [108].

Four of them favored the combination therapy in term of quality of life [1819, 79, 108]. Another two did not report the relevant data [81, 122].

RCT studies were included in the meta-analyses by Cheung (n = 67), Cho (n = 30), and Meng (Explore (NY), 2011) (n = 11), but not in the meta-analyses by Sun and Wu. The information regarding the inclusion of RCTs was not reported in the meta-analysis by Meng (J Altern Complement Med, 2008).

The meta-analysis by Cheung had the largest number of included studies (n = 67), followed by those by Meng (n = 37), Cho (n = 30), Meng (n = 12), Sun (n = 10), and Wu (n = 9) (Supplementary Table S34). However, not all included studies were completely overlapped among the 6 meta-analyses.

Given the superiority in the number of RCTs, the meta-analysis by Cheung might be more reliable. In details, TACE plus TCMs should be favored in terms of OS, tumor response, and quality of life.

TACE + CIK cell therapy versus TACE alone

Two meta-analyses compared the outcomes of TACE in combination with CIK cell therapy versus TACE alone [14, 63]. The combination therapy was beneficial in terms of OS, RFS, TTP, quality of life, and liver and immune function [14, 63]. Additionally, one of them evaluated whether or not adjunctive CIK cell therapy could improve the outcomes of TACE in combination with RFA [63]. Adjunctive CIK cell therapy was beneficial in terms of OS and RFS [63].

RCT studies were included in the meta-analyses by Chen (n = 9) and Li (n = 6).

The meta-analysis by Li had a larger number of included studies than that by Chen (11 versus 9) (Supplementary Table S35). However, not all included studies were completely overlapped between them.

The results regarding the OS were completely consistent among them. In details, TACE in combination with CIK cell therapy should be favored.

Sorafenib

Seven meta-analyses compared the outcomes of sorafenib versus placebo (Supplementary Table S1) [22, 28, 101, 118, 141, 143, 160]. The use of sorafenib was beneficial in terms of OS, TTP, and disease control rate [22, 101, 118, 141, 143, 160]. However, the time to symptomatic progression was statistically similar between the two groups [22, 118, 160]. The incidence of adverse events was significantly increased by the use of sorafenib [28, 101, 118, 141, 143, 160].

RCT studies were included in the meta-analyses by Shen (n = 5), Duffy (n = 4), Wang (n = 4), Zhang T (Anticancer Drugs, 2010) (n = 3), Zhang X (Hepatobiliary Pancreat Dis Int, 2012) (n = 3), Cinco (n = 2), and Zou (n = 2).

The meta-analysis by Shen had a larger number of included studies than those by Wang, Duffy, Zhang T (Anticancer Drugs, 2010), Zhang X (Hepatobiliary Pancreat Dis Int, 2012), Zou, and Cinco (5 versus 4, 4, 3, 3, 2, and 2) (Supplementary Table S36). All studies which were included in the meta-analysis by Wang, Duffy, Zhang T (Anticancer Drugs, 2010), Zhang X (Hepatobiliary Pancreat Dis Int, 2012), and Zou were also included by Shen. In the meta-analysis by Cinco, the included studies were not reported.

The results were completely consistent among them. In details, sorafenib should be favored.

Antiviral therapy

Nineteen meta-analyses compared the outcomes of antiviral therapy versus no antiviral therapy (Supplementary Table S2) [10, 49, 54, 56, 58, 8486, 103, 105, 107, 112, 120, 128, 139, 142, 154, 158159]. Thirteen of them favored the use of antiviral therapy in term of OS [10, 49, 54, 84, 86, 105, 107, 112, 120, 128, 139, 142, 154]; one found that the use of antiviral therapy significantly improved the 5-year survival in HCV patients, but not HBV patients [58]; one demonstrated that the 1-year survival was statistically similar between the two groups [56]; one showed that 1-, 2-, 3-, 4-, and 5-year survival were statistically similar between the two groups [159]; another three did not report the survival data [85, 103, 158].

Five meta-analyses evaluated the DFS/RFS [49, 56, 103, 112, 154]. Four of them favored the use of antiviral therapy in term of DFS/RFS [56, 103, 112, 154]. Another one meta-analysis was performed according to the study design and type of viral hepatitis. In the subgroup analysis of RCTs, the DFS/RFS was statistically similar between the two groups regardless of HCV or HBV [49]. In the subgroup analysis of non-RCTs, antiviral therapy improved the DFS/RFS by in HCV patients, but not HBV patients [49].

Fifteen meta-analyses evaluated the recurrence [10, 54, 56, 58, 8485, 105, 107, 120, 128, 139, 142, 154, 158159]. Ten of them favored the use of antiviral therapy in term of recurrence [10, 56, 8485, 105, 107, 120, 139, 154, 158]; one favored the use of antiviral therapy after TACE, but not surgical resection [54]; two favored the use of antiviral therapy in HCV patients, but not HBV patients [58, 128]; one favored the use of antiviral therapy in terms of 1-, 3-, and 4-year recurrence, but not 2- or 5-year recurrence [159]; one favored the use of antiviral therapy in terms of 1- and 2-year recurrence, but not late recurrence (> 2 year) [142].

RCT studies were included in the meta-analyses by Zhuang (PLoS One, 2013) (n = 13), Huang (n = 10), Shen (n = 9), Wang (n = 9), Zhang (Mol Clin Oncol, 2014) (n = 9), Jiang (n = 8), Li (n = 8), Zhuang (Zhonghua Gan Zang Bing Za Zhi, 2012) (n = 8), Breitenstein (n = 7), Zhang (Int J Cancer, 2009) (n = 6), Miao (n = 5), Singal (n = 5), Xu (n = 5), Moriguchi (n = 4), Miyake (n = 3), Sun (n = 1), and Zhou (n = 1), rather than those by Lan and Wong.

The meta-analysis by Huang had a larger number of included studies than those by Zhang, Zhou, Miao, Shen, Sun, Zhuang (PLoS One, 2013), Jiang, Lan, Miyake, Singal, Wang, Wong, Xu, Li, Zhang, Zhuang (Zhonghua Gan Zang Bing Za Zhi, 2012), Breitenstein, and Moriguchi (23 versus 19, 14, 13, 13, 13, 13, 10, 10, 10, 10, 9, 9, 9, 8, 8, 8, 7, and 4) (Supplementary Table S37). In the meta-analysis by Moriguchi, the included studies were not reported. However, not all included studies were completely overlapped between them.

Given the superiority in the number of RCTs, the meta-analysis by Zhuang (PLoS One, 2013) and Huang might be more reliable. In details, interferon therapy after curative treatment should be favored.

Vitamin

Five meta-analyses compared the outcomes of vitamin versus placebo (Supplementary Table S3) [21, 82, 99, 112, 150]. Two of them favored the use of vitamin in term of OS [112, 150]; two favored the use of vitamin in term of 2-year survival, but not 3-year survival [21, 82]; one showed that the 1- and 2-year survival were statistically similar between the two groups [99].

One meta-analysis favored the use of vitamin in term of RFS [112].

Two meta-analyses favored the use of vitamin in term of 1-year recurrence, but another two did not [21, 82]. Four meta-analyses favored the use of vitamin in terms of 2- and 3-year recurrence [21, 82].

RCT studies were included in the meta-analyses by Wang (n = 6), Zhong (n = 6), Chu (n = 5), Riaz (n = 5), and Meng (n = 4).

The meta-analysis by Zhong had a larger number of included studies than those by Chu, Wang, Riaz, and Meng (7 versus 6, 6, 5, and 4) (Supplementary Table S38). In the meta-analysis by Meng, the included studies were not reported. However, not all included studies were completely overlapped between them.

Given the superiority in the number of RCTs, the meta-analyses by Wang and Zhong should be more reliable. In details, the use of vitamin should be favored in term of OS. However, its benefit was weak.

Octreotide

Three meta-analyses compared the outcomes of octreotide versus placebo (Supplementary Table S4) [29, 43, 52]. As for the 6- and 12-month survival, one of them favored the use of octreotide [52], but another two did not show any significant difference between the two groups [29, 43]. As for the 24-month survival, two of them showed that the survival was statistically similar between the two groups [29, 43], but another one did not report the relevant data [52].

RCT studies were included in the meta-analyses by Ji (n = 9) and Guo (n = 6).

The meta-analysis by Ji had a larger number of included studies than those by Guo and Estanislao (11 versus 6 and 3) (Supplementary Table S39). In the meta-analysis by Estanislao, the included studies were not reported. All studies which were included in the meta-analysis by Guo were also included by Ji.

Given the superiority in the number of RCTs, the meta-analyses by Ji and Guo might be more reliable. In details, the benefit of octreotide remains uncertain.

TCM

One meta-analysis compared the outcomes of kanglaite injection plus hepatic arterial intervention versus hepatic arterial intervention alone (Supplementary Table S5) [34]. The combination therapy was beneficial in terms of tumor response, Karnofsky score improvement, and pain relief [34]. But neither OS nor DFS/RFS was evaluated [34].

One meta-analysis compared the outcomes of Chinese herbal medicine plus chemotherapy versus chemotherapy alone [104]. The combination therapy was beneficial in terms of OS and tumor response [104].

One meta-analysis compared the outcomes of TCM versus other treatment [121]. TCM was superior to other treatments in terms of OS and tumor response [121].

CIK cell therapy

One meta-analysis compared the outcomes of CIK cell therapy versus other treatment (Supplementary Table S6) [76]. CIK cell therapy was superior to other treatments in terms of OS, PFS, disease control rate, tumor response, and quality of life [76].

Tamoxifen

Two meta-analyses compared the outcomes of tamoxifen versus placebo or no treatment (Supplementary Table S7) [73, 90]. Both of them demonstrated that the OS was statistically similar between the two groups [73, 90].

RCT studies were included in the meta-analyses by Nowak (n = 10) and Llovet (n = 7).

Although the meta-analysis by Nowak had a larger number of included studies than that by Llovet (10 versus 7) (Supplementary Table S40), the included studies were not similar between them.

The results were completely consistent among them. In details, tamoxifen should not be favored.

Antibiotics

One meta-analysis compared the outcomes of antibiotics versus no antibiotics after hepatic transarterial therapy [113]. The incidence of fever, bacteremia, septicema, and sepsis were not significantly improved by antibiotics [113].

DISCUSSION

AASLD and EASL guidelines recommend BCLC staging algorithm for the management of HCC. Only 5 treatment modalities have been considered in the current guidelines. In details, the therapeutic modalities of HCC include the LT, surgical resection, and RFA for HCC in the stage 0 and A, TACE for HCC in the stage B, sorafenib for HCC in the stage C, and supportive treatment for HCC in the stage D. However, the BCLC staging algorithm is not flawless and needs to be persistently updated. Nowadays, more and more novel treatment modalities have been widely produced and adopted. Their efficacy and safety have been gradually established. In this circumstance, our study was worthwhile, because it attempted to collect the relevant evidence as many as possible and to provide an overview of outcomes of novel and well-established treatment modalities for HCC based on the results of meta-analyses. More notably, we found that lots of combination therapy might be more effective and safe. For example, the meta-analyses of RCTs demonstrated that RFA plus TACE was superior to mono-therapy, and that surgical resection plus post-operative TACE was superior to surgical resection alone. Given the quality of such meta-analyses, the guidelines should be updated regarding the use of combination therapy.

Limitations

This was a time-consuming work, because a large number of relevant meta-analyses were included. Several limitations should be acknowledged. First, we must clarify that only the results of meta-analyses, but not the accuracy of meta-analyses, were systematically reviewed. Because we cannot repeat every meta-analysis, we cannot guarantee that their findings were accurate. Second, we did not consider the heterogeneity among included studies in every meta-analysis. A significant heterogeneity could affect the stability of a meta-analysis. Third, we arbitrarily evaluated the reliability of meta-analyses according to the number of RCTs and non-RCTs.

Recommendations

LT

1. LDLT has lower DFS than DDLT (grade of recommendation: low).

2. Short- and long-term outcomes may be comparable between primary and salvage LT (grade of recommendation: low).

3. Sirolimus-based immunosuppression should be recommended after LT (grade of recommendation: low).

Surgical resection

1. Surgical resection margin aiming at 2 cm may be superior to 1 cm for the improvement of long-term outcomes (grade of recommendation: moderate).

2. Survival benefit may be comparable between laparoscopic and open resection. Additionally, laparoscopic resection had less blood loss, blood transfusion, and complications and shorter hospital stay (grade of recommendation: low).

3. Anatomic resection, but not non-anatomic resection, should be recommended (grade of recommendation: low).

4. Adjunctive I131 lipiodol therapy may be considered in patients undergoing surgical resection (grade of recommendation: low).

5. Post-operative TACE, but not pre-operative TACE, may be considered in patients undergoing surgical resection (grade of recommendation: high).

6. Immunotherapy may not be considered in patients undergoing surgical resection (grade of recommendation: high).

7. PVE may not be considered in patients undergoing surgical resection (grade of recommendation: low).

Ablation

1. Surgical resection should be superior to RFA in term of OS (grade of recommendation: high).

2. RFA, but not PEI or cryosurgery ablation, should be recommended (grade of recommendation: high).

3. RFA in combination with TACE may be superior to TACE or RFA mono-therapy (grade of recommendation: high).

4. PEI in combination with TACE may be superior to TACE or PEI mono-therapy (grade of recommendation: high).

TAE/TACE

1. TACE/TAE should be superior to placebo (grade of recommendation: high).

2. Survival benefit may be comparable between TACE and TAE (grade of recommendation: high).

3. DEB-TACE was comparable to conventional TACE (grade of recommendation: high).

4. 32P glass microspheres embolization may be superior to TACE for the improvement of OS (grade of recommendation: high).

5. Adjunctive HIFU therapy may further improve the outcomes of TACE (grade of recommendation: moderate).

6. Adjunctive radiotherapy therapy may further improve the outcomes of TACE (grade of recommendation: high).

7. Adjunctive 3D-CRT therapy may further improve the outcomes of TACE (grade of recommendation: moderate).

8. Adjunctive TCMs therapy may further improve the outcomes of TACE (grade of recommendation: high).

9. Adjunctive CIK cell therapy may further improve the outcomes of TACE (grade of recommendation: high).

Sorafenib

1. Sorafenib is superior to placebo for the improvement of OS (grade of recommendation: high).

Other treatments

1. Antiviral therapy should be recommended for the improvement of recurrence (grade of recommendation: high).

2. Vitamin should be recommended for the improvement of OS (grade of recommendation: high).

3. Tamoxifen should not be recommended (grade of recommendation: high).

Uncertainties

1. The superiority of LT to surgical resection for the improvement of OS remains inconclusive. The accurate candidates for LT and surgical resection need to be clearly established.

2. The superiority of surgical resection to RFA for the improvement of OS remains under debate. The indications of RFA should be refined.

3. Although transarterial radioembolization appears to be more advantageous than TACE, their cost-effectiveness should be further explored.

4. Although TACE appears to be more effective than no treatment, the survival benefit of TAE/TACE versus other active treatments should be confirmed.

5. The benefits of combination therapy may be confirmed in the future guidelines.

MATERIALS AND METHODS

Search strategy and study selection

We searched all meta-analysis papers regarding the treatment of HCC via the PubMed, EMBASE, and Cochrane library databases. Search items were as follows: (hepatocellular carcinoma) AND (meta-analysis). The last search was performed on October 1, 2014.

Eligibility criteria were as follows. 1) All meta-analyses regarding the treatment of HCC were included. 2) Duplicate publications were excluded. 3) Narrative reviews were excluded. 4) Only systematic reviews without meta-analyses were excluded. 5) Only systematic review protocols were excluded. 6) Patients without HCC were excluded. 7) Other topics, but not treatment modalities, were excluded.

Primary outcomes were overall survival (OS), diseases-free survival (DFS) or recurrence-free survival (RFS), progression or time-to-progression (TTP), progression-free survival (PFS), recurrence or time-to-recurrence, safety, and other endpoints.

Reliability of meta-analyses

As the results were different among the meta-analyses, the reliability was evaluated according to the quality and quantity of original studies included in every meta-analysis. First, we evaluated the quality of original studies. If a larger number of randomized controlled trials (RCTs) were included, the results of a meta-analysis would be more reliable. Second, if the number of randomized controlled trials was similar, we further evaluated the number of non-RCT studies. If a larger number of non-RCT studies were included, the results of a meta-analysis would be more reliable. Third, if the number of RCT and non-RCT studies included was similar but the results were different among meta-analyses, we further evaluated the statistical methods. Hazard ratio could reflect a general effect over time; by comparison, odds ratio or risk ratio reflected an individual effect at a fixed time point. Thus, if the hazard ratio was calculated, the results of a meta-analysis would be more reliable.

Grade of recommendations

High grade recommendation was considered, if the results of meta-analyses were based on more than 3 single-center RCTs or 1 multi-center RCT. Low grade recommendation was considered, if the results of meta-analyses were based on the non-RCT studies alone. As for something in between, moderate grade recommendation was considered.

Abbreviations

3D-CRT, three-dimensional conformal radiation therapy; AHCS, argon-helium cryotherapy system; CIK, cytokine-induced killer; DDLT, deceased donor liver transplantation; DEB, drug-eluting bead; DFS, diseases-free survival; HCC, hepatocellular carcinoma; HIFU, high-intensity focused ultrasound; LDLT, living donor liver transplantation; LT, liver transplantation; OS, overall survival; PEI, percutaneous ethanol injection; PAI, percutaneous acetic acid injection; PFS, progression-free survival; PVE, portal vein embolization; RCT, randomized controlled trials; RFA, radiofrequency ablation; RFS, recurrence-free survival; TACE, transarterial chemoembolization; TAE, transarterial embolization; TCMs, traditional Chinese medicine; TTP, time-to-progression.

CONFLICTS OF INTEREST

None.

Authors’ contributions

XQ: designed the study, performed the literature search and selection, data extraction, and drafted the manuscript; YZ and HL: performed the literature selection and data extraction; XG and GH: gave critical comments and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission.

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